Trials Of Coronary Artery Bypass Grafting Research Articles

Pleiotropic Effect of Lovastatin, With and Without Cholestyramine, in the Post Coronary Artery Bypass Graft (Post CABG) Trial

This study evaluated patients in the Post Coronary Artery Bypass Graft (Post CABG) trial for evidence of statin pleiotropic effects in preventing atherosclerotic progression in saphenous vein grafts (SVGs). We studied 1,116 of the 1,351 patients in the Post CABG trial who were randomized to aggressive (low-density lipoprotein [LDL] cholesterol target <85 mg/dl) or moderate (target LDL cholesterol <140 mg/dl) lovastatin treatment and who had sufficient data available. The generalized estimating equation models, adjusting for important covariates, were applied to estimate the odds ratios (ORs) and probability of substantial atherosclerotic SVG progression (decrease in lumen diameter >or=0.6 mm) and the difference in minimum lumen diameter change between treatment groups. Aggressive lovastatin treatment compared with moderate treatment was associated with a significant decrease in risk of significant SVG atherosclerotic progression after adjustment for baseline cholesterol level, LDL cholesterol on treatment, high-density lipoprotein cholesterol, and triglyceride changes on treatment and other independent predictors (OR 0.68, 95% confidence interval 0.49 to 0.94, p = 0.019). Results were similar when the change or percent change from baseline of LDL cholesterol level on treatment was adjusted for rather than on-treatment LDL cholesterol and in the subset achieving a year-1 LDL cholesterol level from 90 to 135 mg/dl (OR 0.64, 95% confidence interval 0.42 to 0.98, p = 0.042). Mean decrease in minimum lumen diameter was also significantly smaller in the aggressive than the moderate treatment arm (-0.256 vs -0.343 mm, p = 0.042). In conclusion, aggressive versus moderate lovastatin treatment appeared therapeutic in slowing the atherosclerotic process in SVGs from Post CABG patients, independent of its greater LDL cholesterol-lowering effect.

The Relationship Between Obesity and Atherosclerotic Progression and Prognosis Among Patients With Coronary Artery Bypass Grafts: The Effect of Aggressive Statin Therapy

This study examines whether obesity accelerates atherogenic progression or adverse outcomes after coronary artery bypass graft (CABG) surgery. Obesity is a major risk factor for developing coronary heart disease. Whether obesity accelerates disease progression after CABG is unclear. We examined how body mass index (BMI) related to atherosclerotic graft progression and a clinical composite outcome of death, nonfatal myocardial infarction, stroke, CABG surgery, or angioplasty among 1,314 participants in the Post CABG trial. Participants who had undergone CABG surgery were randomly assigned in a 2 x 2 factorial design to warfarin versus placebo and aggressive low-density lipoprotein cholesterol (LDL-C) lowering with lovastatin 40 to 80 mg/day (to achieve LDL-C of 60 to 85 mg/dl) versus moderate LDL-C lowering with lovastatin 2.5 to 5 mg/day (to achieve LDL-C of 130 to 140 mg/dl). Angiographic progression was assessed by coronary angiography at 4 to 5 years. Higher BMI was associated with a higher likelihood of angiographic progression (p trend = 0.003) after adjustment for demographic factors, treatment assignment, smoking status, and years since CABG surgery, but not with clinical events (p trend = 0.81). In stratified analyses, higher BMI was associated with angiographic progression in the low-dose lovastatin group (p trend <0.001) but not in the high-dose group (p = 0.03 for test for interaction of BMI and statin treatment). In the high-dose lovastatin group, higher BMI appeared to be protective against clinical events (p trend = 0.06, test of interaction: 0.02). Higher BMI is strongly associated with atherogenic progression after CABG surgery. Aggressive statin therapy may be protective against obesity-related acceleration of coronary heart disease.

No improvement in neurocognitive outcomes after off-pump versus on-pump coronary revascularisation: a meta-analysis

The popularity of off-pump (beating heart) coronary artery bypass grafting (CABG) was initially stimulated by numerous theoretical benefits including lower incidence of stroke and neurocognitive dysfunction. With a postoperative stroke rate of less than 1% for elective CABG, it has been very difficult to demonstrate any significant differences in this outcome between techniques. However, changes in neurocognitive function are more common in the postoperative setting and thus provide greater power for demonstrating improvement with changes in surgical technique. The aim of this meta-analysis was to assess whether there were significant differences in neurocognitive outcomes in patients after undergoing off-pump versus on-pump CABG. A database search for prospective randomised controlled trials of off-pump versus on-pump CABG in any language was conducted. Eight trials incorporating 892 patients fulfilled all the inclusion criteria for reporting of neurocognitive outcomes, and were able to be included in this meta-analysis. Sufficient data were available across the seven studies to combine results for five neurocognitive tests (Rey Auditory Verbal Learning, Grooved Pegboard, Trail A and B, and Digit Symbol). Overall there were no convincing differences in outcomes in neurocognitive testing between off-pump and on-pump CABG groups. The results of this meta-analysis show that there are no significant neurocognitive benefits when comparing off-pump versus on-pump CABG.

Design of the Future REvascularization Evaluation in patients with Diabetes mellitus: Optimal management of Multivessel disease (FREEDOM) Trial

Prior randomized trials suggested that revascularization of diabetic patients by coronary artery bypass grafting (CABG) produced results superior to balloon angioplasty. The introduction of drug-eluting stents (DESs) calls into question the relevance of past studies to the current era. The FREEDOM Trial is designed to determine whether CABG or percutaneous coronary intervention (PCI) is the superior approach for revascularization of diabetic patients. The FREEDOM Trial is a multicenter, open-label prospective randomized superiority trial of PCI versus CABG in at least 2000 diabetic patients in whom revascularization is indicated. Consenting diabetic patients with multivessel disease will be randomized on a 1:1 basis to either CABG or multivessel stenting using DESs and observed at 30 days, 1 year, and annually for up to 5 years. At the discretion of the primary physician or interventionalists, patients randomized to the PCI/DES arm will receive any approved DESs. The primary outcome measure is the composite of all-cause mortality, nonfatal myocardial infarction, or stroke. Patients will be observed for a mean of 4 years. At present, coronary revascularization with CABG surgery is the treatment of choice in diabetic patients with multivessel coronary artery disease. Drug-eluting stents have shown promising preliminary results in the diabetic population. The FREEDOM Trial is an international study designed to define the optimal revascularization strategy for the diabetic patient with multivessel coronary disease.

Coronary artery bypass graft vs. percutaneous coronary angioplasty: CABG on the rebound?

To examine the benefits of coronary artery bypass grafting (CABG) against percutaneous coronary intervention (PCI) and particularly the use of drug-eluting stents (DES) in situations where CABG has traditionally been considered the most effective therapy on clinical and economic grounds. Current studies reconfirm that CABG is still the best therapy in terms of improved survival and freedom from reintervention for most patients with proximal left anterior descending, multivessel and left main-stem coronary artery disease (CAD) and that these benefits are even greater in diabetic patients. Health economic analyses also confirm the cost-effectiveness of medical therapy and CABG but not PCI. Furthermore, several meta-analyses have shown that DES do not improve survival or freedom from myocardial infarction compared with bare metal stents, but increase the risk of stent thrombosis, with associated medical and financial implications for prolonged dual antiplatelet medication. In view of the evidence in favour of CABG, this article questions the justifiability of some trials of PCI vs. CABG, especially in diabetic patients and those with left main-stem CAD, and exhorts the need for a multidisciplinary team approach to the management of CAD as a minimum standard of care.

Five-Year Follow-Up of the Medicine, Angioplasty, or Surgery Study (MASS-II)

Clinical trials are organized for many different reasons. Most drug and device trials are designed to demonstrate the safety and efficacy of a drug or device, not to prove that they are the optimal treatments for patients. On the other hand, treatment strategy trials are designed to study the value of one therapeutic regimen compared with another when equipoise or confusion exists regarding which course to pursue. Assumptions are based on prior knowledge and opinion; in the case of coronary artery disease, most trials have been divided into those studying patients who “need” revascularization (ie, EAST [Emory Angioplasty versus Surgery Trial], BARI [Bypass Angioplasty Revascularization Investigation], CABRI [Coronary Artery Bypass Revascularization Investigation], RITA [Second Randomized Intervention Treatment of Angina], GABI [German Angioplasty Bypass Intervention], ARTS [Arterial Revascularization Therapies Study], SOS [Stent or Surgery], ERACI II [Estudio Randomizado Argentino de Angioplastia vs Cirugia II], and meta-analyses of these trails1,2⇓) and those in whom medical therapy is judged to be a reasonable choice. The latter list is short—RITA-2 [Second Randomized Intervention Treatment of Angina]3 and the awaited COURAGE [Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation]4 and BARI 2D [Bypass Angioplasty Revascularization Investigation 2 Diabetes]5 trials. Article p 1082 An assumption is made that patient groups can be identified that will be suitable candidates either for equipoise between 2 revascularization choices or for medical therapy versus revascularization. The study by Hueb et al6 in this issue of Circulation enrolled patients, most of whom would have been eligible for percutaneous coronary intervention (PCI) versus coronary artery bypass graft (CABG) trials, to 3 arms including medical therapy only. Eligible patients had multivessel coronary artery disease (3 vessels, 58%; 2 vessels, 42%), and the left anterior descending artery was involved in 92% of the patients. Therefore, these patients seem …

Aprotinin is useful as a hemostatic agent in cardiopulmonary surgery: yes.

Aprotinin is useful as a hemostatic agent in cardiopulmonary surgery: yes.

A Systematic Review of the Quality of Publications Reporting Coronary Artery Bypass Grafting (CABG) Trials

Purpose Several studies have shown that the quality of reporting randomized controlled trials (RCT) is variable and often poor. Since the results of meta-analyses on the comparison of off-pump (OFCAB) and on-pump (ONCAB) techniques are controversial, we aimed to assess the reporting quality of the RCTs on comparing OFCAB and ONCAB surgery. Methods RCTs published (2000 to 2004) comparing OFCAB and ONCAB were identified from electronic searches of the Medline, Cochrane, Cinahl, HealthStar, and EMBASE. Report quality was assessed with 35 items from the CONSORT statement and 53 additional indicators relevant to CABG surgery. Some of the indicators were composed of several small parts making the maximum possible total score greater than 88. Two authors independently reviewed to assess the reporting quality of each RCT and the level of agreement was assessed using kappa statistics. Disagreements were resolved upon consensus. Descriptive analyses are expressed as median [M] and (minimum [min]-maximum [max]). Pearson, spearman and partial correlation coefficients were used for data analysis. Results Forty-three trials were included with a total of 4544 patients. The Kappa was greater than 0.6 for 67 of 104 (64.4%) indicators. The overall report quality varied between 35 (33.6%) and 80 (76.9%) of 104, with a median score of 51. The CONSORT score reporting quality varied between 17 (40.5%) and 37 (88.0%) of 42, with a median score of 25. The quality of reporting was poor and insufficient for methods (M: 17, min-max: 8–32 of 46) and discussion (4:2–7 of 9) sections. The reporting quality of CABG trials had a strong and positive association with CONSORT score, allocation/blinding, results, protocol and statistical methods. The reporting quality had a strong and positive correlation with the size of trial but it was not correlated with the year of publication. Conclusion The quality of publications reporting for methods and discussion sections was suboptimal. It is critical that in reporting surgical trials, authors follow CONSORT guidelines as well as consider the surgical factors.

A systematic review of the quality of publications reporting Coronary Artery Bypass Grafting (CABG) trials

Several studies have shown that the quality of reporting randomized controlled trials (RCT) is variable and often poor. Since the results of meta-analyses on the comparison of off-pump (OFCAB) and on-pump (ONCAB) techniques are controversial, we aimed to assess the reporting quality of the RCTs on comparing OFCAB and ONCAB surgery. RCTs published (2000 to 2004) comparing OFCAB and ONCAB were identified from electronic searches of the Medline, Cochrane, Cinahl, HealthStar, and EMBASE. Report quality was assessed with 35 items from the CONSORT statement and 53 additional indicators relevant to CABG surgery. Some of the indicators were composed of several small parts making the maximum possible total score greater than 88. Two authors independently reviewed to assess the reporting quality of each RCT and the level of agreement was assessed using kappa statistics. Disagreements were resolved upon consensus. Descriptive analyses are expressed as median [M] and (minimum [min]-maximum [max]). Pearson, spearman and partial correlation coefficients were used for data analysis. Forty-three trials were included with a total of 4544 patients. The Kappa was greater than 0.6 for 67 of 104 (64.4%) indicators. The overall report quality varied between 35 (33.6%) and 80 (76.9%) of 104, with a median score of 51. The CONSORT score reporting quality varied between 17 (40.5%) and 37 (88.0%) of 42, with a median score of 25. The quality of reporting was poor and insufficient for methods (M: 17, min-max: 8–32 of 46) and discussion (4:2–7 of 9) sections. The reporting quality of CABG trials had a strong and positive association with CONSORT score, allocation/blinding, results, protocol and statistical methods. The reporting quality had a strong and positive correlation with the size of trial but it was not correlated with the year of publication. The quality of publications reporting for methods and discussion sections was suboptimal. It is critical that in reporting surgical trials, authors follow CONSORT guidelines as well as consider the surgical factors.

Coronary Artery Surgery

Coronary Artery Surgery

Effect of aprotinin on clinical outcomes in coronary artery bypass graft surgery: A systematic review and meta-analysis of randomized clinical trials

ObjectiveDespite proven blood transfusion benefits, aprotinin may be underused in coronary artery bypass grafting. Reluctance to use aprotinin may stem from safety concerns. The current objective was to evaluate clinical outcomes (mortality, myocardial infarction, renal failure, stroke, atrial fibrillation) in patients undergoing coronary artery bypass grafting who receive aprotinin by performing a quantitative overview of published, randomized, controlled trials. MethodsMEDLINE, EMBASE, and PHARMLINE (1988-2001) and reference lists of relevant articles were searched for coronary artery bypass grafting studies. Criteria for data inclusion were as follows: (1) random allocation of study treatments, (2) placebo control, (3) enrollment only of patients undergoing coronary artery bypass grafting, (4) no combination with another experimental medication or device, and (5) prophylactic and continuous intraoperative use. ResultsData from 35 coronary artery bypass grafting trials (n = 3879) confirm that aprotinin reduces transfusion requirements (relative risk 0.61, 95% confidence interval 0.58-0.66) relative to placebo, with a 39% risk reduction. Aprotinin therapy was not associated with increased or decreased mortality (relative risk 0.96, 95% confidence interval 0.65-1.40), myocardial infarction (relative risk 0.85, 95% confidence interval 0.63-1.14), or renal failure (relative risk 1.01, 95% confidence interval 0.55-1.83) risk, but it was associated with a reduced risk of stroke (relative risk 0.53, 95% confidence interval 0.31-0.90) and a trend toward reduced atrial fibrillation (relative risk 0.90, 95% confidence interval 0.78-1.03). ConclusionsAprotinin reduces transfusion requirements. Concerns that aprotinin therapy is associated with increased mortality, myocardial infarction, or renal failure risk is not supported by data from published, randomized, placebo-controlled clinical trials. Evidence for a reduced risk of stroke and a tendency toward reduction of atrial fibrillation occurrence was observed in patients who received aprotinin.

Quality of Life After Coronary Artery Bypass Graft: Results From the POST CABG Trial

The POST CABG (Post Coronary Artery Bypass Graft) Trial showed that aggressive lowering of low-density lipoprotein (LDL) cholesterol levels reduced the progression of atherosclerosis in saphenous vein grafts. In the extended follow-up phase, aggressive lowering of LDL cholesterol levels was associated with reduced rates of clinical events. Low-dose anticoagulation therapy did not reduce the progression of atherosclerosis. We conducted this analysis to determine the effects of both lipid-lowering and low-dose anticoagulation therapy on health-related quality of life (HRQL). Randomized clinical trial, factorial design. Outpatients in five tertiary care medical centers. A cohort of 852 patients enrolled in the POST CABG Trial completed an HRQL questionnaire at baseline, and at the year 2 and year 4 follow-up visits. Aggressive LDL cholesterol lowering vs moderate LDL cholesterol lowering, and low-dose warfarin vs placebo. Domains included emotional status, basic physical and social functioning, perceived health status, symptoms of pain, a variety of physical symptoms, and global life satisfaction. Overall, there were no indications of systematic differences among treatment groups for any of the HRQL parameters at baseline, year 2, or year 4. These data indicate that patients did not experience detrimental or beneficial effects on HRQL parameters while receiving LDL cholesterol-lowering therapy that had demonstrable benefits for treatment of atherosclerosis.

Late-Breaking Clinical Trial Abstracts

Late-Breaking Clinical Trial Abstracts

High-risk elderly patients PROSPER from cholesterol-lowering therapy

Several large-scale statin trials have shown that cholesterol-lowering therapy produces substantial benefits for high-risk individuals, 1 Scandinavian Simvastatin Survival Study GroupRandomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian simvastatin survival study (4S). Lancet. 1994; 344: 1383-1389 Summary PubMed Scopus (11230) Google Scholar , 2 Shepherd J Cobbe SM Ford I et al. for the West of Scotland Coronary Prevention Study GroupPrevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med. 1995; 333: 1301-1307 Crossref PubMed Scopus (7448) Google Scholar , 3 Sacks FM Pfeffer MA Moye LA et al. for the Cholesterol and Recurrent Events Trial InvestigatorsThe effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med. 1996; 335: 1001-1009 Crossref PubMed Scopus (7173) Google Scholar , 4 The Post Coronary Artery Bypass Graft Trial InvestigatorsThe effect of aggressive lowering of low-density lipoprotein cholesterol levels and low-dose anticoagulation on obstructive changes in saphenous-vein coronary-artery bypass grafts. N Engl J Med. 1997; 336: 153-162 Crossref PubMed Scopus (968) Google Scholar , 5 The Long-term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study GroupPrevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med. 1998; 339: 1349-1357 Crossref PubMed Scopus (5549) Google Scholar , 6 Downs JR Clearfield M Weis S et al. for the AFCAPS/TexCAPS Research GroupPrimary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. JAMA. 1998; 279: 1615-1622 Crossref PubMed Scopus (4978) Google Scholar , 7 Serruys PWJC de Feyter P Macaya C et al. for the Lescol Intervention Prevention Study (LIPS) InvestigatorsFluvastatin for prevention of cardiac events following successful first percutaneous coronary intervention: a randomised controlled trial. JAMA. 2002; 287: 3215-3222 Crossref PubMed Scopus (694) Google Scholar , 8 Heart Protection Study Collaborative GroupMRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20 536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002; 360: 7-22 Summary Full Text Full Text PDF PubMed Scopus (7596) Google Scholar not just in middle age but also in old age, 8 Heart Protection Study Collaborative GroupMRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20 536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002; 360: 7-22 Summary Full Text Full Text PDF PubMed Scopus (7596) Google Scholar , 9 Hunt D Young P Simes J et al. for the LIPID investigatorsBenefits of pravastatin on cardiovascular events and mortality in older patients with coronary heart disease are equal to or exceed those seen in younger patients: results from the LIPID trial. Ann Intern Med. 2001; 134: 931-940 Crossref PubMed Scopus (230) Google Scholar and the PROSPER trial reported in today's Lancet reinforces those findings for the elderly. Typically, in the previous trials, a 1 mmol/L reduction in plasma LDL cholesterol concentration maintained for about 5 years reduced the risks of coronary events, of strokes, and of revascularisation procedures by about one quarter (although the proportional reduction in risk appeared to be somewhat smaller during the first year after starting treatment). In PROSPER, 5804 high-risk individuals aged 70–82 (mean 75) years with mean LDL cholesterol of 3·8 mmol/L at entry were randomly allocated to receive 40 mg pravastatin daily or placebo for an average of 3·2 years. Despite a lowering of LDL cholesterol by an average of about 1·0 mmol/L during the study, however, allocation to pravastatin was associated with a proportional reduction of “only” 15% (SE 7, 95% CI 3–26) in the primary outcome of coronary death, non-fatal myocardial infarction, or stroke (408 [14·1%] pravastatin vs 473 [16·2%] placebo affected individuals, p=0·014). At least in part, this smaller than anticipated risk reduction may be due to chance, since the confidence interval around the estimate is wide and remains consistent with a reduction of one quarter. But it may also reflect the greater diluting effect on the overall risk reduction of a smaller reduction in risk during the first year after lowering LDL cholesterol in a trial involving 3 years of treatment (ie, 1 of 3 years) than in the previous statin trials that typically involved 5 years of treatment (ie, 1 of 5 years). Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trialPravastatin given for 3 years reduced the risk of coronary disease in elderly individuals. PROSPER therefore extends to elderly individuals the treatment strategy currently used in middle aged people. Published online Nov 19, 2002 http://image.thelancet.com/extras/02art8325web.pdf Full-Text PDF

Revascularization Versus Implantable Cardioverter-Defibrillators to Prevent Sudden Death in Patients With Severe Left Ventricular Dysfunction

Sudden death remains a dreaded consequence of coronary artery disease, and efforts to predict its incidence and to prevent its occurrence remain a major concern. A number of the challenges in management are highlighted in the article by Veenhuyzen et al1 in the present issue of Circulation . In their study, mortality and modes of death were assessed in 5410 patients with ischemic left ventricular function who were enrolled in the Studies of Left Ventricular Dysfunction (SOLVD) study.2 There were 1870 patients who had had prior coronary artery bypass grafting (CABG) and 3540 who had not had prior CABG. The SOLVD trial database is a good source for these data, both because it is large and because the cause of death (ie, whether cardiac and whether sudden or not) was established. See p 1489 The key findings of Veenhuyzen et al1 are that CABG was associated with a 25% reduction in the risk of death (from 24.3% to 18.4%) and a 46% reduction in the risk of sudden death (from 7.5% to 4.1%). These findings are independent of ejection fraction, severity of heart failure symptoms, age, and other clinical variables. In a stratified analysis by severity of left ventricular dysfunction, there was some evidence for interaction, but similar results were noted overall. Prior CABG was not associated with an alteration in the risk of death from progressive heart failure. The results were applied to a group of patients with left ventricular dysfunction from the Coronary Artery Surgery Study Registry who had not undergone surgery, offering a predicted annual rate of death of 8.2% and sudden death …

Lessons from the post coronary artery bypass graft study in evaluating and controlling technical variability in angiographic trials

Although many investigators have evaluated the technical variability of quantitative angiographic techniques used to study atherosclerosis regression in native coronary arteries, few have studied the variability inherent in repeated studies of atherosclerotic saphenous vein grafts. This study describes 2 studies performed during the course of the Post Coronary Artery Bypass Graft (CABG) Clinical Trial that were designed to assess the reproducibility of: (1) repeated angiographic views within a short time period; and (2) reproducibility of the total process of quantitative analysis of saphenous vein graft angiograms. Statistical methods are described that provide a more meaningful assessment of the impact of measurement variability in the analytic process versus the variability related to changes induced by pharmacologic interventions. One such method, the increase in standard deviation (SD) among patients (ISDP), showed that repeated angiographic views increased the variability of calculation of lesion minimal diameter by 1.5%, whereas the ISDP for repetition of the entire process of quantitative angiographic readings increased variability 6.4%. These data from the Post CABG trial reveal that technical variability is small and has negligible impact on the conclusions of the study.

Aggressive lipid-lowering initiation abates new cardiac events (ALLIANCE)—rationale and design of atorvastatin versus usual care in hypercholesterolemic patients with coronary artery disease

Guidelines of the National Cholesterol Education Program (NCEP) and other national and international organizations are now placing increased emphasis on the importance of effective reduction of cholesterol, in particular low-density lipoprotein (LDL) cholesterol, in patients with coronary artery disease (CAD). 1 National Cholesterol Education ProgramSecond Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II). Circulation. 1994; 89: 1333-1445 Crossref PubMed Google Scholar , 2 Wood D. de Backer G. Faergeman O. Graham I. Mancia G. Pyörälä K. Members of the Task ForcePrevention of coronary heart disease in clinical practice. Recommendations of the Second Joint Task Force of European and other Societies on coronary prevention. Eur Heart J. 1998; 19: 1434-1503 Crossref PubMed Scopus (1403) Google Scholar These recommendations are based on overwhelming evidence from epidemiologic studies and clinical trials. 3 Martin M.J. Hulley S.B. Browner W.S. Kuller L.H. Wentworth D. Serum cholesterol, blood pressure and mortality implications from a cohort of 361,662 men. Lancet. 1986; 2: 933-936 Abstract PubMed Scopus (960) Google Scholar , 4 Verschuren W.M. Jacobs D.R. Bloemberg B.P. Kromhout D. Menotti A. Aravanis C. Blackburn H. Buzina R. Dontas A.S. Fidanza F. Karvonen M.J. Nedelijkovic S. Nissinen A. Toshima H. Serum total cholesterol and long-term coronary heart disease mortality in different cultures. Twenty-five-year follow-up of the seven countries study. JAMA. 1995; 274: 131-136 Crossref PubMed Google Scholar , 5 Scandinavian Simvastatin Survival Study GroupRandomized trial of cholesterol lowering in 4444 patients with coronary heart disease the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994; 344: 1383-1389 Abstract PubMed Scopus (11197) Google Scholar , 6 Shepherd J. Cobbe S.M. Ford I. Isles C.G. Lorimer A.R. MacFarlane P.W. McKillop J.H. Packard C.J. West of Scotland Coronary Prevention Study GroupPrevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med. 1995; 333: 1301-1307 Crossref PubMed Scopus (7430) Google Scholar , 7 Sacks F.M. Pfeffer M.A. Moyé L.A. Rouleau J.L. Rutherford J.D. Cole T.G. Brown L. Warnica J.W. Arnold J.M. Wun C.C. Davis B.R. Braunwald E. Cholesterol, and Recurrent Events Trial InvestigatorsThe effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med. 1996; 335: 1001-1009 Crossref PubMed Scopus (7162) Google Scholar , 8 Long-term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study GroupPrevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med. 1998; 339: 1349-1357 Crossref PubMed Scopus (5532) Google Scholar , 9 Downs J.R. Clearfield Weis S. Whitney E. Shapiro D.R. Beere P.A. Langendorfer A. Stein E.A. Kruyer W. Gotto Jr, A.M. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels. Results of AFCAPS/TexCAPS. JAMA. 1998; 279: 1615-1622 Crossref PubMed Scopus (4966) Google Scholar More recent studies have led to the suggestion that additional clinical benefit may be gained by lowering LDL cholesterol beyond currently recommended levels. The Post-Coronary Artery Bypass Graft trial demonstrated that in patients who had undergone bypass grafts, there was significantly less progression of atherosclerosis with an aggressive approach to LDL cholesterol reduction (to a mean LDL cholesterol of 93 to 97 mg/dl [2.4 to 2.5 mmol/L]) compared with a moderate treatment strategy (mean LDL cholesterol level of 132 to 136 mg/dl [3.4 to 3.5 mmol/L]). 10 Post Coronary Artery Bypass Graft Trial InvestigatorsThe effect of aggressive lowering of low-density lipoprotein cholesterol levels and low-dose anticoagulation on obstructive changes in saphenous-vein coronary-artery bypass grafts. N Engl J Med. 1997; 336: 153-162 Crossref PubMed Scopus (963) Google Scholar In the Atorvastatin Versus Revascularization Treatments study, patients with stable CAD were randomized to receive atorvastatin 80 mg/day or angioplasty and/or usual medical care. 11 Pitt B. Waters D. Brown W.V. van Boven J. Schwartz L. Title L.M. Eisenberg D. Shurzinske L. McCormick L.S. Aggressive lipid-lowering therapy compared with angioplasty in stable coronary artery disease. N Engl J Med. 1999; 341: 70-76 Crossref PubMed Scopus (838) Google Scholar The 36% relative reduction in risk of ischemic events showed a trend toward significance and was associated with an LDL cholesterol level of 77 mg/dl (1.99 mmol/L) compared with 119 mg/dl (2.08 mmol/L) in the angioplasty/usual-care group.

Lipid-lowering treatment in coronary artery disease: how low should cholesterol go?

The randomised clinical trial data, which supports preventing coronary heart disease (CHD) events by lowering low density lipoprotein cholesterol (LDL-C) levels, is substantial, consistent and highly significant. HMG-CoA reductase inhibitors (statins), which are the preferred medications for lowering LDL-C levels, are well tolerated, with greater efficacy than other lipid-altering medications. In 1993, the National Cholesterol Education Program (NCEP) guidelines recommended LDL-C target levels to be achieved with therapy in high-risk individuals. In particular, the LDL-C goal of therapy in patients with CHD was < or = 100 mg/dl (2.6 mmol/L), with no specific guidance as to the lower limit or whether additional clinical benefit could be expected. Because little clinical trial data existed at that time to offer support, and because some epidemiological data raised concern about the potential detriments associated with very low total cholesterol and LDL-C levels, the NCEP Adult Treatment Panel remained appropriately vague on the 'how low should you go' question. In the last few years, several additional clinical trials have provided sufficient efficacy and safety data to re-examine that question. Analyses of on-treatment LDL-C levels and subsequent CHD events from three landmark trials with HMG-CoA reductase inhibitors suggest that progressively lower LDL-C levels are associated with lower CHD events in a curvilinear fashion. The Post Coronary Artery Bypass Graft (Post-CABG) trial and Atorvastatin Versus Revascularisation Trial (AVERT) examined a more intensive versus less intensive drug regimen for LDL-C reduction, and concluded that the more aggressively treated patients had better angiographic and end-point outcomes. Most importantly, there did not appear to be any change in noncardiovascular end-points associated with lower LDL-C levels. In several ongoing clinical trials, patients with CHD have been randomised to receive HMG-CoA reductase inhibitors with targets for LDL-C levels of 100 mg/dl versus 75 mg/dl (1.94 mmol/L). These trials have sufficient patient numbers and power to definitely determine if reducing LDL-C levels to approximately 75 mg/dl can provide an acceptable benefit-to-risk-ratio.

The effect of aggressive and moderate lowering of LDL-cholesterol and low dose anticoagulation on plasma lipids, apolipoproteins and lipoprotein families in post coronary artery bypass graft trial

The reported results (The Post Coronary Artery Bypass Graft Trial Investigators. The effect of aggressive lowering of low-density lipoprotein cholesterol levels and low-dose anticoagulation on obstructive changes in saphenous-vein coronary-artery bypass grafts. New Engl J Med 1997;336:153–162) of the Post Coronary Artery Bypass Graft (Post CABG) trial have shown that aggressive lowering was more effective than moderate lowering of low density lipoprotein (LDL) cholesterol in reducing the progression of atherosclerosis in saphenous-vein grafts (27 vs. 39%; P<0.001); low dose warfarin had no effect on the progression of atherosclerosis. The present report describes the effect of long-term (an average of 4.3 years) aggressive treatment with high (40–80 mg/day) and moderate treatment with low (2.5–5 mg/day) doses of lovastatin on lipids, apolipoproteins (apo) and apoA- and apoB-containing lipoprotein families. To achieve the target LDL-cholesterol levels (60–85 mg/dl for aggressive group and 134–140 mg/dl for moderate group), cholestyramine (8 g/day) was given to 25% of subjects on aggressive and 5% of subjects on moderate treatment. Although with both treatment strategies there were significant decreases ( P<0.001) in the levels of total cholesterol, LDL-cholesterol, apoB, LDL-apoB and cholesterol-rich Lp-B family, percent changes in the levels of these variables were greater in the aggressive- than in the moderate-treatment groups. These treatments had only marginal effects in increasing the levels of high density lipoprotein cholesterol, apoA-I and Lp-A-I and Lp-A-I:A-II families. The long-term aggressive treatment exerted no effect on the concentrations of triglycerides, apoC-III, apoC-III in VLDL+LDL and triglyceride-rich Lp-B c families. Neither treatment affected the levels of Lp(a). The potentially modifying influence of warfarin and apoE phenotypes on lovastatin-induced changes in lipoprotein variables was found to be of little significance. It is likely that the beneficial effect of lovastatin in reducing the progression of atherosclerosis in grafts is mediated through its specific lowering effect on cholesterol-rich Lp-B particles.

Aggressive cholesterol lowering delays saphenous vein graft atherosclerosis in women, the elderly, and patients with associated risk factors. NHLBI post coronary artery bypass graft clinical trial. Post CABG Trial Investigators.

The NHLBI Post Coronary Artery Bypass Graft trial (Post CABG) showed that aggressive compared with moderate lowering of low-density lipoprotein-cholesterol (LDL-C) decreased obstructive changes in saphenous vein grafts (SVGs) by 31%.1 Using lovastatin and cholestyramine when necessary, the annually determined mean LDL-C level ranged from 93 to 97 mg/dL in aggressively treated patients and from 132 to 136 mg/dL in the others (P<0.001). The present study evaluated the treatment effect in subgroups defined by age, gender, and selected coronary heart disease (CHD) risk factors, ie, smoking, hypertension, diabetes mellitus, high-density lipoprotein cholesterol (HDL-C) <35 mg/dL, and triglyceride serum levels >/=200 mg/dL at baseline. As evidenced by similar odds ratio estimates of progression (lumen diameter decrease >/=0.6 mm) and lack of interactions with treatment, a similar beneficial effect of aggressive lowering was observed in elderly and young patients, in women and men, in patients with and without smoking, hypertension, or diabetes mellitus, and those with and without borderline high-risk triglyceride serum levels. The change in minimum lumen diameter was in the same direction for all subgroup categories, without significant interactions with treatment. Aggressive LDL-C lowering delays progression of atherosclerosis in SVGs irrespective of gender, age, and certain risk factors for CHD.